Vascular complications of diabetes are devastating, and can affect every major organ. Patients with diabetes have an increased incidence of atherosclerosis, and of cardiovascular, peripheral vascular, and cerebrovascular disease. Vascular complications and disease account for most of the mortality and morbidity of diabetic individuals.
Numerous factors contribute to the development of vascular disease in patients with diabetes, including hyperglycemia, hypertension, obesity, and dyslipidemia. For example, elevated blood glucose levels (i.e., hyperglycemia) are believed to be a primary cause of microvascular complications, including retinopathy, nephropathy, and neuropathy, and to play a role in the premature and accelerated development of macrovascular complications, such as cardiovascular disease and peripheral vascular disease. Elevated blood glucose levels and oxidant stress, both characteristic of the diabetic microenvironment, accelerate advanced glycation end-product (AGE) formation. Hyperglycemia and AGEs can cause changes (e.g., damage) to the normal structure and function of the endothelium and can lead to endothelial dysfunction. In addition, hyperglycemia and AGEs have been associated with various vascular complications, including damage to the body's microvasculature and macrovasculature. Further, hyperglycemia and dyslipidemia are associated with intima-media thickness, a recognized marker for cardiovascular and cerebrovascular disease.
Cardiovascular complications of diabetes mellitus are severe and significantly contribute to the morbidity and mortality rates of the disease. These complications include coronary heart disease (CHD), congestive heart failure, stroke, peripheral arterial disease, cardiomyopathy, nephropathy, retinopathy, and neuropathy.
Vascular disease can occur in diabetic patients in association with other complications, such as, for example, diabetic nephropathy, a common and often severe condition. Cardiovascular disease is the leading cause of death among diabetic patients with end-stage renal disease (ESRD). (McMillan et al. (1990) BMJ 301:540-544; Hirschl et al. (1992) Am J Kidney Dis. 20:564-568; and Rischen-Vos et al. (1992) Nephrol Dial Transplant 7:433-437.)
Patients with diabetes are at critical risk for congestive heart failure. A number of factors contribute to the high incidence of diabetic cardiomyopathy, including prolonged hypertension, chronic hyperglycemia, severe coronary atherosclerosis, etc. Mortality from stroke is increased almost 3-fold when patients with diabetes are matched to those without diabetes. (Stamler et al. (1993) Diabetes Care 16:434-444.) Further, diabetes increases the likelihood of severe carotid atherosclerosis. (Folsom et al. (1994) Stroke 16:434-444. and O'Leary et al. (1992) Stroke 25:66-73.)
The incidence of peripheral vascular disease (PVD) is about 4 times greater in patients with diabetes than patients without diabetes. (See, e.g., Gibbons (1998) Peripheral vascular disease. In H. E. Lebovitz, ed., Therapy for diabetes mellitus (3rd edition), pp. 290-302.) Peripheral vascular disease is a condition in which the arteries in the legs, and sometimes the arms, are narrowed by atherosclerosis. It contributes to lower-extremity ulceration, impaired wound healing, and decreased ability to fight infection. The reasons for this include delayed or prevented delivery of oxygen (ischemia), nutrients, and antibiotics to the infected area and impaired immune response. (See Gibbons, supra.) Other conditions associated with diabetes, such as hypertension, obesity, and dyslipidemia, further exacerbate the diabetic patient's chances of developing PVD.
Current treatment strategies directed to treatment or reduction of the progression and severity of vascular complications of diabetes, or to prevention of the development of such complications, employ various approaches, including optimized glycemic control (through modification of diet and/or insulin therapy), hypertension control (including administration of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) to reduce hypertension), cholesterol-lowering treatments, etc. However, such therapies are not universally successful, and often are ineffective at reversing the vascular complications and pathology (e.g., damage) associated with diabetes or improving the function of affected vessels, organs, and tissues. Further, due to such factors as the aging of the population and a believed increase in prevalence of obesity and sedentary life habits in the United States and in the global population, the prevalence of diabetes is increasing worldwide. Thus, diabetes is a major risk factor for vascular disease on a global scale. Therefore, there is a need in the art for methods for treating vascular complications of diabetes, methods for reducing the progression and severity of these vascular complications, and methods for preventing the development of such complications. Additionally, there is a need in the art for methods and agents effective at reversing the vascular complications associated with diabetes, including reversing the pathology and damage to the vasculature, and for improving the function of vessels, organs, and tissues affected by vascular complications associated with diabetes.
The present invention meets this need by showing for the first time that specific inhibition of CTGF both reduces vascular dysfunction and measurably improves vascular function in animal models of diabetic disease. In particular, the present invention demonstrates that administration of an anti-CTGF antibody effectively reduced arterial stiffness, vascular permeability, extravasation, e.g., edema, and vascular calcification, in an animal model of diabetes. The present methods and agents also effectively reversed the pathology and damage to the vasculature associated with diabetes.
The present invention further demonstrates that specific inhibition of CTGF improves cardiac function. In particular, the present invention demonstrates that administration of an anti-CTGF antibody led to measurable improvement in cardiac function as evidenced by demonstrated improvements in the following parameters: ventricular relaxation, ventricular contractility, end diastolic pressure, end diastolic volume, ejection fraction, arterial elastance, stroke volume, and cardiac output.